This application is the National Phase filing of International Patent Application No. PCT/JP00/07283, filed Oct. 19, 2000.
The present invention relates to a medicine, especially to novel naphthalene derivatives having a steroid C17,20-lyase inhibitory activity, or its production and pharmaceutical compositions containing the same.
Androgen and estrogen, each of which is a sex hormone, are essential in a living body and have various physiological activities such as differentiation and proliferation of cell, etc. On the other hand, it has been found that each of androgen and estrogen works as a exacerbation factor in some diseases.
It is known that, in the biosynthesis of androgen in vivo, steroid C17,20-lyase acts at the final stage. That is, steroid C17,20-lyase converts 17-hydroxypregnenolone and 17-hydroxyprogesterone derived from cholesterol to dehydroepiandrosterone and androstenedione, respectively. Therefore, a medicine having a steroid C17,20-lyase inhibitory activity suppresses the formation of androgen and estrogen which is produced from androgen, and is useful for preventing and treating diseases whose exacerbation factor is androgen or estrogen. As the disease whose exacerbation factor is androgen or estrogen, there may be mentioned, for example, prostate cancer, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, breast cancer, uterine cancer, mastopathy, uterus myoma, endometriosis, adenomyosis of uterus, polycystic ovary syndrome, etc.
It has been already known that some steroid type compounds and some non-steroid type compounds inhibit steroid C17,20-lyase. The steroid type compounds are disclosed in, for example, WO 92/15404, WO 93/20097, EP-A 288053, EP-A 413270, etc. As non-steroid type compounds, for example, (1H-imidazol-1-yl)methyl-substituted benzimidazole derivatives are shown in Japanese Published Unexamined Patent Application No. 85975/1989, carbazole derivatives are shown in WO94/27989 and WO96/14090, azole derivatives are shown in WO95/09157, 1H-benzimidazole derivatives are shown in U.S. Pat. No. 5,491,161, dihydronaphthalene derivatives are shown in WO99/18075.
Heretofore, steroid C17,20-lyase inhibitors which can actually be used as medicine have not been known. Thus, it has been expected the early development of steroid C17,20-lyase inhibitors which are useful as medicine.
The present invention provides:
(1) A compound of the formula: 
wherein R is a hydrogen atom or a protecting group, R1 is a lower alkyl group or a cyclic alkyl group, R2 is a group represented by the formula: 
(wherein a ring A1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents, and a ring A2 and a ring A3 may have substituents), a group represented by the formula: 
(wherein the ring B1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents and a ring B2 and a ring B3 may have substituents) or a group of the formula: 
(wherein each of R3, R5 is a hydrogen atom, a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, R4 is an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents or a carbamoyl group optionally having substituents, R6 is an optionally halogenated lower alkyl group and n is an integer of 0 to 3.), or a salt thereof,
(2) A compound as defined in (1), wherein R is (i) a hydrogen atom, (ii) a formyl group or (iii) a C1-6 alkyl-carbonyl group, a phenyl-carbonyl group, a C1-6 alkyl-oxycarbonyl group, an allyl-oxycarbonyl group, a phenyloxycarbonyl group, a C7-10 aralkyl-oxy-carbonyl group, a trityl group, a N,N-dimethylaminosulfonyl group, a C7-16 aralkyl-oxy-C1-6 alkyl group each of which optionally has substituents selected from the group consisting of a halogen atom, a C1-6 alkyl-carbonyl and nitro,
R1 is a straight chain or branched C1-6 alkyl group or a C3-6 cycloalkyl group,
the ring A1 is a 5- or 6-membered ring containing an oxygen atom together with carbon atoms as ring constituting atoms and the ring may further contain a nitrogen atom and a sulfur atom as the ring constituting atoms, optionally having 1 to 4 substituents selected from the group consisting of (i) a C1-4 alkyl group optionally having substituents selected from the group consisting C1-4 alkanoyl, carboxyl and C1-4 alkoxy-carbonyl, (ii) a C1-3 alkoxy group, (iii) a C1-4 alkanoyl group, (iv) a C1-4 alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C1-10 alkyl carbamoyl group, (vii) a mono- or di-C6-14 arylcarbamoyl group, (viii) a mono- or di-C7-16 aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C1-10 alkyl sulfamoyl group, (xi) a mono- or di-C6-14 arylsulfamoyl group and (xii) a mono- or di-C7-16 aralkyl sulfamoyl group,
the ring A2 and the ring A3 may have 1 to 3 substituents selected from the group consisting of (i) a C1-4 alkyl group optionally having substituents selected from the group consisting C1-4 alkanoyl, carboxyl and C1-4 alkoxy-carbonyl, (ii) a C1-3 alkoxy group, (iii) a C1-4 alkanoyl group, (iv) a C1-4 alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C1-10 alkyl carbamoyl group, (vii) a mono- or di-C6-14 arylcarbamoyl group, (viii) a mono- or di-C7-16 aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C1-10 alkyl sulfamoyl group, (xi) a mono- or di-C6-14 arylsulfamoyl group and (xii) a mono- or di-C7-16 aralkyl sulfamoyl group at any substitutable position,
the ring B1 is a 5- or 6-membered ring containing an oxygen atom together with carbon atoms as ring constituting atoms and the ring may further contain a nitrogen atom and a sulfur atom as the ring constituting atoms, optionally having 1 to 4 substituents selected from the group consisting of (i) a C1-4 alkyl group optionally having substituents optionally having substituents selected from the group consisting C1-4 alkanoyl, carboxyl and C1-4 alkoxy-carbonyl, (ii) a C1-3 alkoxy group, (iii) a C1-4 alkanoyl group, (iv) a C1-4 alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C1-10 alkyl carbamoyl group, (vii) a mono- or di-C6-14 arylcarbamoyl group, (viii) a mono- or di-C7-16 aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C1-10 alkyl sulfamoyl group, (xi) a mono- or di-C6-14 arylsulfamoyl group and (xii) a mono- or di-C7-16 aralkyl sulfamoyl group,
the ring B2 and the ring B3 may have 1 to 3 substituents selected from the group consisting of (i) a C1-4 alkyl group optionally having substituents selected from the group consisting C1-4 alkanoyl, carboxyl and C1-4 alkoxy-carbonyl, (ii) a C1-3 alkoxy group, (iii) a C1-4 alkanoyl group, (iv) a C1-4 alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C1-10 alkyl carbamoyl group, (vii) a mono- or di-C6-14 arylcarbamoyl group, (viii) a mono- or di-C7-16 aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C1-10 alkyl sulfamoyl group, (xi) a mono- or di-C6-14 arylsulfamoyl group and (xii) a mono- or di-C7-16 aralkyl sulfamoyl group at any substitutable position,
R3 and R5 is independently
(i) a hydrogen atom,
(ii) a C1-4 alkyl group optionally having substituents selected from the group consisting of C1-4 alkanoyl, carboxyl and C1-4 alkoxy-carbonyl,
(iii) a group selected from the group consisting of a hydroxy group, a C1-4 alkoxy group, a C1-4 alkanoyloxy group, a carbamoyloxy group and a mono- or di-C1-4 alkyl-carbamoyloxy group,
(iv) a group selected from the group consisting of a thiol group, a C1-4 alkylthio group and a C1-4 alkanoylthio group,
(v) a group selected from the group consisting of an amino group, a C1-4 alkyl amino group, a di-C1-4 alkylamino group and a C1-4 alkanoylamino group,
(vi) an acyl group selected from the group consisting of a formyl group, a C1-6 alkanoyl group, a C1-4 alkylsulfonyl group, a carbamoyl group, a mono- or di-C1-10 alkyl carbamoyl group, a mono- or di-C6-14 arylcarbamoyl group, a mono- or di-C7-16 aralkyl carbamoyl group, a sulfamoyl group, a mono- or di-C1-10 alkylsulfamoyl group, a mono- or di-C6-14 arylsulfamoyl group and a mono- or di-C7-16 aralkyl sulfamoyl group, or
(vii) a halogen atom,
R4 is
(I) a C6-14 aryl group optionally having substituents selected from the group consisting of (i) a C1-4 alkyl group optionally having substituents selected from the group consisting C1-4 alkanoyl, carboxyl and C1-4 alkoxy-carbonyl, (ii) a C1-3 alkoxy group, (iii) a C1-4 alkanoyl group, (iv) a C1-4 alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C1-10 alkyl carbamoyl group, (vii) a mono- or di-C6-14 arylcarbamoyl group, (viii) a mono- or di-C7-16 aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C1-10 alkyl sulfamoyl group, (xi) a mono- or di-C6-14 arylsulfamoyl group and (xii) a mono- or di-C7-16 aralkyl sulfamoyl group,
(II) a 3- to 13-membered heterocyclic group which contains 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms, optionally having substituents selected from the group consisting of (i) a C1-4 alkyl group optionally having substituents selected from the group consisting C1-4 alkanoyl, carboxyl and C1-4 alkoxy-carbonyl, (ii) a C1-3 alkoxy group, (iii) a C1-4 alkanoyl group, (iv) a C1-4 alkylsulfonyl group, (v) a carbamoyl group, (vi) a mono- or di-C1-10 alkyl carbamoyl group, (vii) a mono- or di-C6-14 arylcarbamoyl group, (viii) a mono- or di-C7-16 aralkylcarbamoyl group, (ix) a sulfamoyl group, (x) a mono- or di-C1-10 alkyl sulfamoyl group, (xi) a mono- or di-C6-14 arylsulfamoyl group and (xii) a mono- or di-C7-16 aralkyl sulfamoyl group,
(III) a carbamoyl group,
(IV) a mono- or di-C1-10 alkyl-carbamoyl group optionally having substituents selected from the group consisting of hydroxy, halogen atom, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 acyl, carboxyl and C1-6 alkoxy-carbonyl,
(V) a mono- or di-C3-7 cycloalkyl-carbamoyl group optionally having substituents selected from the group consisting of hydroxy, halogen atom, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 acyl, carboxyl and C1-6 alkoxy-carbonyl,
(VI) a mono- or di-C6-14 aryl carbamoyl group optionally having substituents selected from the group consisting of hydroxy, halogen atom, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 acyl, carboxyl and C1-6 alkoxy-carbonyl,
(VII) a mono- or di-C7-16 aralkyl carbamoyl group optionally having substituents selected from the group consisting of hydroxy, halogen atom, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 acyl, carboxyl and C1-6 alkoxy-carbonyl,
(VIII) a 3- to 7-membered cyclic amino-carbonyl group optionally having substituents selected from the group consisting of hydroxy, halogen atom, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 acyl, carboxyl and C1-6 alkoxy-carbonyl,
(IX) a 5- or 6-membered heterocyclic-carbamoyl group which contains 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms optionally having substituents selected from the group consisting of hydroxy, halogen atom, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 acyl, carboxyl and C1-6 alkoxy-carbonyl, or
(X) a C1-6 alkoxy-carbamoyl group optionally having substituents selected from the group consisting of hydroxy, halogen atom, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, C1-6 acyl, carboxyl and C1-6 alkoxy-carbonyl,
R6 is an optionally halogenated C1-6 alkyl group, and
n is an integer of 0 to 3,
(3) A compound as defined in (1), wherein R is a hydrogen atom or a protecting group, R1 is a lower alkyl group or a cyclic alkyl group, R2 is a group of the formula: 
(wherein the ring A is a 5- or 6-membered ring containing an oxygen atom), a group of the formula: 
(wherein the ring B is a 5- or 6-membered ring containing an oxygen atom) or a group of the formula: 
(wherein each of R3 and R5 is a hydrogen atom, a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, and R4 is an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents or a carbamoyl group optionally having substituents),
(4) A compound as defined in (1), wherein R is a hydrogen atom, R1 is a straight chain or branched C1-6 alkyl group, R2 is a group represented by the formula: (3), and R4 is a carbamoyl group optionally having substituents,
(5) A compound as defined in (1), wherein R is a hydrogen atom or a trityl group, R1 is a straight chain or branched C1-6 alkyl group or a C3-6 cycloalkyl group,
the ring A is 
the ring B is 
R3 is a hydrogen atom, a C1-4 alkyl group or a halogen atom,
R4 is
(i) a C6-14 aryl group,
(ii) a 5- or 6-membered heterocyclic group which contains 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms,
(iii) a carbamoyl group,
(iv) a mono- or di-C1-10 alkyl-carbamoyl group which may be substituted by hydroxy, C3-7 cycloalkyl or C1-6 alkoxy-carbonyl,
(v) a mono- or di-C3-7 cycloalkyl-carbamoyl group,
(vi) a mono- or di-C6-14 aryl carbamoyl group,
(vii) a mono- or di-C7-16 aralkyl carbamoyl group,
(viii) a 3- to 7-membered cyclic amino-carbonyl group,
(ix) a 5- or 6-membered heterocyclic-carbamoyl group which contains 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than carbon atoms,
(x) a C1-6 alkoxy-carbamoyl group,
R5 is a hydrogen atom or a C1-4 alkyl group,
(6) A compound as defined in (1), wherein R is a hydrogen atom, R1 is a straight chain or branched C1-6 alkyl group, R2 is a group represented by the formula (3), R3 is a hydrogen atom, R4 is a mono- or di-C1-10 alkyl-carbamoyl group or a C3-7 cycloalkyl-carbamoyl group and R5 is a hydrogen atom,
(7) A compound as defined in (1), which is
(i) 6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl-2-naphthamide,
(ii) 6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-isopropyl-2-naphthamide,
(iii) N-cyclopropyl-6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-2-naphthamide,
(iv) 6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide,
(v) 6-[1-hydroxy-1-(1H-imidazol-4-yl)-3-methylbutyl]-N-methyl-2-naphthamide,
(vi) (S)-(xe2x88x92)-6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-methyl-2-naphthamide,
(vii) (S)-(xe2x88x92)-N-cyclopropyl-6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-2-naphthamide,
(viii) (S)-(xe2x88x92)-6-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-N-isopropyl-2-naphthamide,
(ix) (S)-(xe2x88x92)-6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide,
(x) (S)-(xe2x88x92)-6-[1-hydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide-fumarate, or a salt thereof,
(8) A compound as defined in (1), wherein the configuration of the carbon which connects to the hydroxy group is (S)-configuration,
(9) A pro-drug of the compound as defined in (1),
(10) A pharmaceutical composition which comprises a compound of the formula: 
wherein R is a hydrogen atom or a protecting group, R1 is a lower alkyl group or a cyclic alkyl group, R2 is a group represented by the formula: 
(wherein a ring A1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents, and a ring A2 and a ring A3 may have substituents), a group represented by the formula: 
(wherein the ring B1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents and a ring B2 and a ring B3 may have substituents) or a group of the formula: 
(wherein each of R3 and R5 is a hydrogen atom, a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, R4 is an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents or a carbamoyl group optionally having substituents, R6 is an optionally halogenated lower alkyl group and n is an integer of 0 to 3.), or a salt thereof, or a pro-drug thereof,
(11) The pharmaceutical composition as defined in (10), which is a steroid C17,20-lyase inhibitor,
(12) The composition as defined in (10), which is an antitumor agent,
(13) The composition for an antitumor agent as defined in (10), which is a treating or preventing agent for breast cancer or prostate cancer,
(14) An androgen reducer which combines a compound of the formula: 
wherein R is a hydrogen atom or a protecting group, R1 is a lower alkyl group or a cyclic alkyl group, R2 is a group represented by the formula: 
(wherein a ring A1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents, and a ring A2 and a ring A3 may have substituents), a group represented by the formula: 
(wherein the ring B1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents and a ring B2 and a ring B3 may have substituents) or a group of the formula: 
(wherein each of R3 and R5 is a hydrogen atom, a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, R4 is an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents or a carbamoyl group optionally having substituents, R6 is an optionally halogenated lower alkyl group and n is an integer of 0 to 3.), or a salt thereof, or a pro-drug thereof with a LH-RH modulator,
(15) A process for producing a compound of the formula: 
wherein R1 is a lower alkyl group or a cyclic alkyl group, R2a is a group of the formula: 
(wherein a ring A1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents, and a ring A2 and a ring A3 may have substituents), a group represented by the formula: 
(wherein the ring B1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents and a ring B2 and a ring B3 may have substituents) or a group of the formula: 
(wherein each of R3 and R5 is a hydrogen atom, a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, R4a is a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group, an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, a carbamoyl group optionally having substituents or halogen atom, R6 is an optionally halogenated lower alkyl group and n is an integer of 0 to 3), and R is a hydrogen atom or a protecting group, or a salt thereof, which comprises reacting a compound of the formula: 
wherein R1 and R2a have the meanings given above, or a salt thereof with a reaction product of a compound of the formula: 
wherein X is a leaving group and R has the meaning given above,
(16) A method for inhibiting a steroid C17,20-lyase which comprises administering a compound of the formula: 
wherein R is a hydrogen atom or a protecting group, R1 is a lower alkyl group or a cyclic alkyl group, R2 is a group represented by the formula: 
(wherein a ring A1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents, and a ring A2 and a ring A3 may have substituents), a group represented by the formula: 
(wherein the ring B1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents and a ring B2 and a ring B3 may have substituents) or a group of the formula: 
(wherein each of R3 and R5 is a hydrogen atom, a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, R4 is an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents or a carbamoyl group optionally having substituents, R6 is an optionally halogenated lower alkyl group and n is an integer of 0 to 3.), or a salt thereof, or a pro-drug thereof to mammals, and
(17) Use of a compound represented by the formula: 
wherein R is a hydrogen atom or a protecting group, R1 is a lower alkyl group or a cyclic alkyl group, R2 is a group represented by the formula: 
(wherein a ring A1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents, and a ring A2 and a ring A3 may have substituents), a group represented by the formula: 
(wherein the ring B1 is a 5- or 6-membered ring containing an oxygen atom optionally having substituents and a ring B2 and a ring B3 may have substituents) or a group of the formula: 
(wherein each of R3 and R5 is a hydrogen atom, a lower alkyl group optionally having substituents, a hydroxyl group optionally having substituents, a thiol group optionally having substituents, an amino group optionally having substituents, an acyl group or a halogen atom, R4 is an aromatic hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents or a carbamoyl group optionally having substituents, R6 is an optionally halogenated lower alkyl group and n is an integer of 0 to 3.), or a salt thereof, or a pro-drug thereof for preparing a pharmaceutical composition for inhibiting a steroid C17,20-lyase.